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Structure-Activity Relationships for Thyroid Hormone Deiodination by Mammalian Type I Iodothyronine Deiodinases¹

Thyroid Division (N.T., M.J.B., J.W.H., P.R.L.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Internal Medicine III (E.K., T.J.V.), Erasmus University Medical School, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Theo J. Visser, Ph.D., Department of Internal Medicine III, Erasmus University Medical School, PO Box 1738, Room Bd 234, 3000 DR Rotterdam, The Netherlands.

The bioactivity of thyroid hormone is determined to a large extent by the monodeiodination of the prohormone T₄ by the hepatic selenoenzyme type I iodothyronine deiodinase (ID1), i.e. by outer ring deiodination (ORD) to the active hormone T₃, or by inner ring deiodination (IRD) to the inactive metabolite rT₃. ID1 also catalyzes the IRD of T₃ and the ORD of rT₃, both to T₂, as well as the deiodination of different iodothyronine sulfates, e.g. IRD of T₃S and ORD of T₂S. Previous studies have indicated important differences in catalytic specificity between dog ID1 (dID1) and human ID1 (hID1), in particular with respect to the ORD of rT₃. This study was done to investigate the relationship between structure and catalytic function of this enzyme by comparing the deiodination of T₄, T₃, rT₃, T₃S, and T₂S by native dID1 and hID1 in liver microsomes as well as by recombinant wild-type, chimeric and mutated d/hID1 enzymes expressed in HEK293 cells. With both native and recombinant wild-type enzymes, the substrate specificity was T₃S > T₂S rT₃ >> T₄ > T₃ for dID1, and rT₃ >> T₂S T₃S > T₄ T₃ for hID1. Whereas ORD of T₄ and of T₄, T₃, and T₃S showed relatively little variation between the different d/hID1 constructs, large differences were found for the ORD of rT₃ and T₂S. Both reactions were favored by the presence of the amino acids G, E and, in particular, F, present in hID1 at positions 45, 46, and 65, instead of the dID1 residues N, G, and L, respectively. However, although ORD of rT₃ was not affected by the presence (hID1) or absence (dID1) of the TGMTR(48–52) sequence, the ORD of T₂S was markedly inhibited by the presence of this sequence. Therefore, we have identified structural elements in ID1 that have substrate-specific impacts on deiodination. Our results suggest the specific interaction of the mono-substituted inner ring of the substrates rT₃ and T₂S but not the disubstituted inner ring of T₃, T₃S, or T₄, with the aromatic ring of F65 in ID1, perhaps by - interactions.

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